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Targeting TJP1 attenuates cell–cell aggregation and modulates chemosensitivity against doxorubicin in leiomyosarcoma

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Abstract

Tight junction protein 1 (TJP1) is a membrane-associated cytosolic protein important for cell–cell communication in intercellular barriers in epithelial and non-epithelial cells. Here, we explored the functional involvement of TJP1 in non-epithelial tumors such as soft tissue sarcoma, especially in leiomyosarcoma (LMS). TJP1 expression in soft tissue sarcoma was analyzed in normal and tumor tissues as well as from public datasets such as the TCGA provisional dataset, in which TJP1 expression was compared with other subtypes such as undifferentiated sarcomas, and myxofibrosarcomas. SK-LMS-1 cell lines with reduced TJP1 expression showed attenuated anchorage-independent colony formation as well as reduced intercellular aggregation on non-coated culture plates compared with control as well as parental SK-LMS-1 cells. Transcriptome profiling following TJP1 knockdown in SK-LMS-1 cells suggested the involvement of several signaling pathways, including NF-κB pathway and growth factor receptor signaling. In addition, TJP1 downregulation induced enhanced response against anti-cancer agents, doxorubicin and gefitinib. Taken together, these results suggest that TJP1 contributes to sarcoma genesis and might be useful therapeutic target.

Key messages

• TJP1 expression at RNA level higher in tumor than in normal tissues of sarcoma.

• Targeting TJP1 attenuates cell–cell aggregation and anchorage-independent growth.

• Targeting TJP1 is beneficial in anti-cancer therapy in LMS.

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Acknowledgements

We thank Mi Ae Kim of the Microscopy Core (National Cancer Center), Tae Sik Kim of the FACS core (National Cancer Center), and Mi Sun Park of Animal Laboratory (National Cancer Center) for their expert assistance and helpful suggestions. Also, we thank the NCC sarcoma research group (National Cancer Center) for their advice as well as assistance in managing information, and sampling process.

Funding

This work was supported in part by National Cancer Center Grant NCC-1710252, NCC-1810865 (to HJYOU) and National Research Foundation of Korea Grant funded by the Korea Government (MSIP, South Korea) (No. 2019R1H1A2039666, to HJYOU).

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Authors and Affiliations

  1. Division of Translational Science, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi, 10408, South Korea

    Eun-Young Lee, Jung Yeon Yu, A Rome Paek, So Hee Lee & Hye Jin You

  2. Department of Medical Biotechnology, Yeungnam University, 280 Daehak-ro, Gyeongsan, 38541, South Korea

    Eun-Young Lee

  3. Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy (NCC-GCSP), National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi, 10408, South Korea

    Hyonchol Jang & Hye Jin You

  4. Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, South Korea

    Hyonchol Jang

  5. Clinical Genomic Analysis Branch, Research Institute, National Cancer Center, Goyang, South Korea

    Soo Young Cho

  6. National Cancer Center Hospital, National Cancer Center, Goyang, South Korea

    June Hyuk Kim, Hyun Guy Kang, Tak Yun, Sung Eun Oh & Seog Yun Park

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  1. Eun-Young Lee
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Correspondence to Hye Jin You.

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The study was vetted by the Ethics Review Board of the National Cancer Center, Korea (IRB No.: NCC2017-0062). The study was performed according to the principles of the Declaration of Helsinki.

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Lee, EY., Yu, J.Y., Paek, A.R. et al. Targeting TJP1 attenuates cell–cell aggregation and modulates chemosensitivity against doxorubicin in leiomyosarcoma. J Mol Med 98, 761–773 (2020). https://doi.org/10.1007/s00109-020-01909-8

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